title: Novel 6β-acylaminomorphinans with analgesic activity.
abstract: Aminomorphinans are a relatively young class of opioid drugs among which substances of high in vitro efficacy and favorable in vivo action are found. We report the synthesis and pharmacological evaluation of novel 6β-acylaminomorphinans. 6β-Morphinamine and 6β-codeinamine were stereoselectively synthesized by Mitsunobu reaction. The aminomorphinans were subsequently acylated with diversely substituted cinnamic acids. In vitro binding studies on cinnamoyl morphinamines showed moderate affinity for all opiate receptors with some selectivity for mu opioid receptors, while cinnamoyl codeinamines only showed affinity for mu opioid receptors. In vivo analgesia studies showed significant analgesic activity of 6β-cinnamoylmorphinamine mediated by mu and delta receptors. The lead compound was found to be roughly equipotent to morphine (ED₅₀ 3.13 ± 1.09 mg/kg) but devoid of the dangerous side-effect respiratory depression, a major issue associated with traditional opioid therapy.
authors.affiliation: Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary; Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA. Electronic address: varadi.andras@pharma.semmelweis-univ.hu.
authors.forename: András
authors.initials: A
authors.lastname: Váradi
authors.forename: Sándor
authors.initials: S
authors.lastname: Hosztafi
authors.forename: Valerie
authors.initials: V
authors.lastname: Le Rouzic
authors.forename: Gergő
authors.initials: G
authors.lastname: Tóth
authors.forename: Ákos
authors.initials: Á
authors.lastname: Urai
authors.forename: Béla
authors.initials: B
authors.lastname: Noszál
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.forename: Steven G
authors.initials: SG
authors.lastname: Grinnell
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D051379:Mice; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology; D009292:Narcotic Antagonists; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects*; D011957:Receptors, Opioid / Q000819:agonists; D012131:Respiratory Insufficiency / Q000139:chemically induced; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: C000589303:6-cinnamoylmorphinamine; D000700:Analgesics; D009019:Morphinans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009020:Morphine
keywords: Aminomorphinan; Analgesia; Cinnamoyl morphinamine; MOR/DOR agonist; Opioid; Respiratory depression